Wednesday, March 19, 2008

The Great Generic "Controversy"

The short version of this post is that there is no controversy. 99% of generic drugs are safe and effective. Given available data and a long history of positive results, there is simply no reason for your pharmacist (or your doctor) to recommend against use of a generic in 99% of all cases.

Let's start off the post with a list of comments I hear from patients on a fairly regular basis on the subject of generic drugs.

•"I want the 'real thing.'"
•"My doctor told me that generics don't work."
•"I'm allergic to generics."
•"How can the generic be as good if it's cheaper?"
•"No one is willing to guarantee that the generic and the brand are exactly the same, so I want the brand."

For starters, generics are "the real thing." They contain the same drug molecule that is responsible for changing your body's function as the brand. They are not cheap imitations. A technician I once worked with explained that people's objection to generic drugs was frequently because of their experience with generic foods; generic Oreos don't taste like "real" Oreos, after all. But unlike drug laws that mandate generics to be the same as brands, there's no law saying that generic Oreos have to taste just like real Oreos.

You aren't "allergic to generics." You just aren't. It isn't possible. An allergy to some component of a specific drug formulation (a dye, a flavoring, whatever) is totally possible. Saying you are allergic to generics is like saying you are allergic to fruit. The category is too big to be plausible.

If you think your doctor told you never to get generics, your doctor either failed to explain the difference between generic and brand adequately, or you are an idiot. A third possibility is that your doctor is a dermatologist. Some huge percentage of dermatologists advocate marking prescriptions for acne creams and similar products as "brand medically necessary" because they claim there is a huge difference. Hm. I'd think that if there were any product where a little bit of variation wouldn't matter much to my health would be my cosmetic face cream. Who knew?

The FDA has already answered the cost question. I won't answer it again.

Pharmacy colleague Abel Pharmboy has already elaborated on the basics of generic drugs. Patients are often confused by the 80-125% rule, so I rarely bring it up in clinical practice, but what it boils down to is this. It has nothing to do with the amount of drug in the tablet. It has nothing to do with the potency of the drug. Generics are equal to the brands in this respect. What differs between brands and generics, in most cases, are the "inert" fillers and binders that hold a tablet together or comprise the granules contained inside a capsule.

You rarely get the full dose of a drug. If you put a 100 mg tablet of drug X in your mouth and swallow it, there is a good chance that only a small percentage of drug X is absorbed (anywhere from 5% to 95%, depending on the drug). The big, technical word for this is bioavailability.

Suppose taking 100 mg of drug X means you have blood levels of 10 nanograms (ng) per deciliter (dL). What the 80-125% rule means is that if you take 100 mg of generic drug X your blood levels could be anywhere from 8 to 12.5 ng/dL and the drug would still be considered acceptable by FDA standards.

And that's the thing. For most drugs, it doesn't matter where you are in that range as long as you're above some minimum and below some toxic maximum, both of which are typically pretty far from the ideal range. Generic ibuprofen versus brands? Not gonna matter. Antibiotics? You're more likely to get sub-therapeutic blood levels because the patient isn't taking the drug properly than you are some bioavailability issue. Blood pressure meds? Your goal BP is based on averages, so it's all going to even out over time. Going generic is not going to cause your blood pressure to fluctuate wildly.

The whole thing only becomes an issue if this is not the first time a patient has taken a drug. If you have never taken a particular drug before, your blood level of that drug is obviously zero. You will start taking the drug, and after a set period of time, your blood level of the drug will reach a "steady" concentration as long as you continue taking your medication appropriately. It is only if you are suddenly switched from brand to generic that you might see a change--and you'd have the same issue if you started on generic and then switched to the brand.

For most drugs, as I mentioned above, there's no difference between our hypothetical 8 and 12 ng/dL. For others--those said to have a narrow therapeutic index--8 ng/dL may mean "no effect" and 12 ng/dL might mean "liver failure."

Of course, with drugs like this, patients must be closely monitored--using blood tests, in many cases--to make sure that they're getting just the right amount of drug. But that doesn't mean that the brand is superior. It means that the patient's therapy should be consistent. If the patient starts on the brand, they should stay on the brand, and if they start on the generic, they should stay on the generic, with no flip-flopping back and forth between the two. Most pharmacists are loathe to switch people back and forth repeatedly on drugs like Synthroid, Dilantin, or Lanoxin. And some states explicitly forbid it in their pharmacy law codes. Seizures in particular are all-or-nothing, so I totally agree with these sentiments.

Some people want to extend this no-substitution issue to all psychoactive drugs. Antidepressants are the big one; some patients really, really want the branded Paxil over the generic (generic brands just don't know how to act), for example (nevermind that brand name Paxil has not been on the market for a few years now).

It's easy to see why this might happen, drug efficacy aside. More expensive medicine makes patients feel better. I'm not saying antidepressants are placebos; the jury is still out on that one, though most evidence favors efficacy, even if it is slight (the drugs would never have been approved otherwise). But paying more for a drug--or a placebo--results in a better outcome for most patients. Perhaps paying more for the drug raises their expectations and subtly influences their mood. With largely subjective disorders like depression, subjective improvements are real improvements.

The case of the Wellbutrin scenario is somewhat unique in that we are talking about an extended-release product.

The process of making a tablet can be extremely simple or extremely complex. It is possible to make aspirin tablets by compressing crystalline aspirin with corn starch and water. At the other end of the spectrum are tablets that are designed with microscopic pores designed to release their contents at a constant (and precise) rate as the tablet passes through the intestinal tract, with the empty tablet shell being excreted with the next bowel movement. Extended-release formulations are generally on the complicated end of the scale, and the design process for these tablets is a great deal more involved. Many drug companies even patent their own extended-release mechanisms, like the OROS mechanism.

Because a generic manufacturer cannot simply use the same extended-release mechanism as the brand-name manufacturer (remember, these mechanisms are often patented), they must design their own tablet designed to release the drug at a similar rate. According to the ConsumerLabs data, the generic buproprion XL tablets released their drug more rapidly than Wellbutrin XL tablets. But the same amount of drug did get released, and the full dose was delivered.

Honestly, this doesn't surprise me in the least. The question is whether or not the increased rate of release is significant. For that, I'm going to have to go to Lexi-Comp's Drug Information Handbook, online edition. This could get a bit technical, but don't worry, I'll sum it up at the end.

The half-life of bupropion is greatly dependent on the person's liver function, ranging from 12 to 30 hours with an average of 21 hours. Bupropion's metabolites, i.e. the by-products of breakdown by the liver, are also active drugs, though they are less potent than bupropion (20-50% potency). These metabolites have half-lives similar to or longer than the primary drug, one of them having a half-life of anywhere from 30 to 40 hours.

What all these numbers ultimately mean is that bupropion hangs around in the body for a long time, and generic tablets releasing the drug over 2 and 1/2 hours instead of 5 hours is not going to significantly effect the "lower bound"--the lowest blood level measured in the peaks and valleys produced by daily administration. Remember that blood levels of a drug look kind of like a normal distribution curve, only flatter or shifted up, depending on the drug. To continue the math analogy, what the more rapid release is going to do is increase the slope of the curve.

This is not going to effect treatment of depression if the benchmark we're looking at is "is the patient maintaining minimum drug levels?" The more likely outcome is that the patient is going to experience a slight increase in side-effects compared to the brand name (if they've been switched from generic to brand recently) due to the fact that their blood levels are climbing more rapidly after administration. Whether or not this is going to be a problem depends on the patient. Last I checked, however, no one was complaining that patients switched to generic Wellbutrin XL were having seizures (which would be extremely unlikely unless the patient had an existing seizure disorder, which is a NO-NO when it comes to prescribing this drug). The specific issue probably never would have come up if it weren't for ConsumerLabs doing a bunch of assays.

Like with most brand-generic issues, the complaint from patients was most likely that the drug "wasn't working" or that they "just didn't feel right." These are the same complaints that come up all the time. That doesn't mean that they shouldn't be investigated; it just means that it's hard for heathcare professionals to filter things out given the poor signal to noise ratio.

I'm still not convinced that the differences between brand and generic Wellbutrin XL are clinically significant, but then, I'm just a pharmacy student. What's troubling is that this information didn't come out sooner, and, as Abel mentioned, the fact that it was kept under wraps until an independent lab started poking around seriously undermines both the generic drug companies and the FDA's trustworthiness in the eyes of the public. That's the true tragedy here; patients are going to think that this failure to disclose information is indicative of serious problems with the generic drug industry when in fact the complete opposite is true. The generic drug industry has a long record of producing safe and effective drugs. Most community pharmacies dispense generic alternatives for over 90% of the prescriptions they fill without any hitches--I know mine does.

Generic drugs are a great thing for patients. Let's not let one little slip--a slip of questionable significance from a clinical perspective--ruin that.


Abel Pharmboy said...

Very well stated, N.B. I neglected to mention in my post that the potential for differences in generic bioavailability are not often of clinical significance. Where they are most relevant are, as you state, for drugs with a narrow therapeutic index or for sustained release dosage forms meant to treat chronic illnesses like depression or hypertension.

You are closer to Rx school than I but I recall a classic case in pharmaceutics that led to rules being established for dosage form changes even within the same brand name long before generics were available - I believe it was a change in excipient for phenytoin that led to an increase in bioavailability and increased incidence of gingival hyperplasia. I'm having trouble finding the original report - did they teach you about this?

N.B. said...

I'm afraid that I have not heard the specific phenytoin anecdote to which you refer. I'll have to look into that!

PalMD said...

Great post! I wish more of my patients were computer-literate.

Generics have been such a boon for medication compliance.

If a patient needs, say, metoprolol for their heart, and says he can't afford it, I can remind him that it's only 4 bucks a month. That's less than one pack of cigs.

Matt said...

Has anybody had a negative experience with generic drugs? I’m looking to speak with a Minnesota patient who has been switched from a brand name drug to a generic and who could share their experience. If you are interested, please email me at

Anonymous said...

classic.medical opinion proffered by a nonclinician.your "faith"in generic drug makers (and the FDA) is simple,at best.your dogmatic attachment to bioavailability "stats" in proving[sic] your "opinion" betrays your inability to assess clinical impact on real patients.stick to filling scripts,I'll keep seeing patients.

George said...

I am all for generic drug use as it is identical to branded drugs in terms of dose, strength, safety, and efficacy. All drug manufacturers should be encouraged to apply near infrared spectroscopy in their manufacturing process to ensure the quality of the drugs. As a matter of fact, the near infrared technology has proven its capabilities as it is utilized in the quality control process of many industries.